Composite particles which contain both cellulose and inorganic compound

ABSTRACT

Provided are composite particles which exhibit excellent fluidity and high liquid retentivity and which exhibit high fluidity even in a liquid-holding sate. Also provided are composite particles which permit direct compressing in an open feed manner and which suffer from little compressing trouble and exhibit high shapability. When shaped together with an active ingredient, the composite particles provide shaped bodies which have uniform weight, uniform active ingredient content, and high hardness and which suffer from less galling.

TECHNICAL FIELD

The present invention relates to composite particles having highfluidity and liquid carrying properties, and keeping compactibility andfluidity of the particles even after retention of the liquid to preventtableting problems.

BACKGROUND ART

Conventionally, in the fields of pharmaceuticals, foods, and otherchemical industries, cellulose powder is widely used as an excipient formolding when a molded article containing an active ingredient isprepared. In addition, in the case where the active ingredient is aliquid ingredient, the liquid ingredient is carried by a singleinorganic compound to obtain a powder. The obtained powder is moldedinto a molded article by using a cellulose powder as an excipient.

Unfortunately, the single inorganic compound has an excessively largeapparent specific volume, which limits the amount of the activeingredient to be powdered at one time. There is also a handling problemsuch that the inorganic compound scatters, or the like. For this reason,use of cellulose-inorganic compound porous composite particles as theexcipient has been examined.

Patent Literature 1 describes an invention of fine particles produced byco-processing a microcrystalline cellulose particle and calciumcarbonate having a particle size less than 30 μm in a specific massratio in order to reduce cost of a pharmaceutical excipient.

Patent Literature 2 describes an invention of an excipient compositioncomposed of a fine particle agglomerates including a microcrystallinecellulose and silicon dioxide as a pharmaceutical excipient havingimproved compressibility.

Patent Literature 3 describes an invention of cellulose inorganiccompound porous composite particles which are an aggregate of a specificcellulose dispersed particle and a water-insoluble inorganic compoundparticle, and having an intraparticle pore volume of 0.260 cm³/g ormore. According to Patent Literature 3, the cellulose and the inorganiccompound are formed into composite particles to obtain a particle havinga large intraparticle pore volume, and high compactibility,disintegration properties, and fluidity.

Patent Literature 4 describes an invention of a solid formulation whichis not a composite product but a physical mixture of an inorganiccompound and a microcrystalline cellulose, and comprises a drug, calciumsilicate, and starch and/or microcrystalline cellulose, in which 10 to45% by weight of calcium silicate is blended based on the drug, and 40to 250% by weight of starch and/or microcrystalline cellulose is blendedbased on calcium silicate. According to the description, even if a drughaving poor compactibility such as phenacetin and acetaminophen isdirectly tableted, 70 to 90 parts by weight of the drug can be blendedwithout capping.

CITATION LIST Patent Literature

-   Patent Literature 1: U.S. Pat. No. 4,744,987-   Patent Literature 2: JP 10-500426 A-   Patent Literature 3: JP 2005-232260 A-   Patent Literature 4: JP 3-52823 A

SUMMARY OF INVENTION Technical Problem

Usually, a tablet is produced by tableting by filling a powder into adie and compressing the powder with a punch. In the case where the drugeasily adheres to the punch, it causes a phenomenon called sticking suchthat the surface of the molded article is peeled off. Usually, a singleinorganic compound is used as an excipient, but the single inorganiccompound cannot always prevent the sticking. Moreover, because thesingle inorganic compound has a large apparent specific volume, flushingproperties of the powder are increased in tableting to reduce fillingproperties into the die, leading to problems such as variation in theweight of the molded article and a phenomenon called capping: part ofthe molded article is peeled off. For this reason, a large amount of theinorganic compound cannot be added.

Cellulose powder is an excipient having high compactibility. Once thecellulose powder gets wet, however, the compactibility is reduced, thefunction as the excipient is no longer demonstrated. Moreover, comparedto the inorganic compound, the cellulose powder has lower liquidretention. Moreover, the composite products of cellulose and aninorganic compound known in the related art have a low liquid retentionrate, and low fluidity of the particle after retention of the liquid. Inaddition, problems such as sticking and capping cannot be sufficientlyeliminated.

An object of the present invention is to provide composite particleshaving a high liquid retention rate and having high fluidity of theparticles even after retention of a liquid. In addition, another objectof the present invention is to provide composite particles that can betableted with gravity feeder in a direct tableting method, hardly causetableting problems, and have high compactibility. Further another objectof the present invention is to provide a molded article in which theweight of the molded article and the content of an active ingredient areuniform, hardness is high, and friability is low when the compositeparticles and the active ingredient are formed into the molded article.

Solution to Problem

In order to solve the problems above, the present inventors have foundout that if cellulose and an inorganic compound are formed into acomposite product, the apparent specific volume, the pore volume, andthe liquid retention rate can be increased, and compactibility andfluidity of the particles even after retention of a liquid can beincreased. Thus, the present invention has been made.

Namely, the present invention is as follows.

-   (1) Composite particles comprising a cellulose and an inorganic    compound, and having an apparent specific volume of 7 to 13 cm³/g.-   (2) The composite particles according to (1), wherein the cellulose    has an average width of 2 to 30 μm and an average thickness of 0.5    to 5 μm.-   (3) The composite particles according to (1) or (2), comprising 10    to 60 parts by mass of the cellulose and 40 to 90 parts by mass of    the inorganic compound.-   (4) The composite particles according to any one of (1) to (3),    wherein the inorganic compound is at least one selected from the    group consisting of silicon dioxide hydrate, light anhydrous silicic    acid, synthetic aluminum silicate, magnesium hydroxide-aluminum    hydroxide co-precipitate, magnesium aluminometasilicate, magnesium    aluminosilicate, calcium silicate, non-crystalline silicon oxide    hydrate, magnesium silicate, and magnesium silicate hydrate.-   (5) The composite particles according to any one of (1) to (4),    wherein the inorganic compound is calcium silicate.-   (6) The composite particles according to any one of (1) to (5),    wherein a pore size is 0.003 to 1 μm, and a pore volume is 1.9 to    3.9 cm³/g.-   (7) The composite particles according to any one of (1) to (6),    wherein a retention rate of tocopherol acetate is 500 to 1000%.-   (8) The composite particles according to any one of (1) to (7),    wherein a weight average particle size is 30 to 250 μm.-   (9) The composite particles according to any one of (1) to (8),    further comprising starch.-   (10) A molded article comprising the composite particles according    to any one of (1) to (9) and an active ingredient.-   (11) The molded article according to (10), wherein the active    ingredient is an ingredient for a medicament or an ingredient for    health food.-   (12) A molded article comprising composite particles comprising a    cellulose and an inorganic compound, and an active ingredient,    wherein the active ingredient is a liquid having a viscosity at    25° C. of 3 to 10000 mPa·s, and the molded article contains 105 to    250 mg of the active ingredient per 500 mg of one molded article.-   (13) The molded article according to (12), wherein the liquid    ingredient is tocopherol acetate.

Advantageous Effects of Invention

The composite particles according to the present invention have a largeapparent specific volume and pore volume, and a high retention rate oftocopherol acetate as an index of the liquid retention rate. Scatteringproperties are reduced by forming a composite product, providing goodoperability. Thereby, the composite particles of the present inventioncan be used as an adsorption carrier of the liquid ingredient. Byforming a composite product, high fluidity after retention of the liquidcan be provided, a uniformity in weight of the molded article andcontent of the active ingredient can be provided among molded articles,and a large content of the liquid ingredient can be contained in themolded article. In addition, the molded article according to the presentinvention has sufficient hardness, can prevent sticking and capping, andprovide a molded article having low friability.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is an enlarged SEM photograph at a magnification of 500 times ofComposite Particles B according to Example 2.

FIG. 2 is an enlarged SEM photograph at a magnification of 500 times ofComposite Particles D according to Example 4.

FIG. 3 is an enlarged SEM photograph at a magnification of 500 times ofComposite Particles G according to Example 7.

FIG. 4 is an enlarged SEM photograph at a magnification of 500 times ofComposite Particles I according to Example 9.

FIG. 5 is an enlarged SEM photograph at a magnification of 200 times ofa dried product of a cellulose WET cake.

FIG. 6 is an enlarged SEM photograph at a magnification of 500 times ofcalcium silicate according to Reference Example 2.

FIG. 7 is an enlarged SEM photograph at a magnification of 500 times ofComposite Particles K according to Example 11.

FIG. 8 is an enlarged SEM photograph at a magnification of 500 times ofComposite Particles M according to Example 13.

FIG. 9 is an enlarged SEM photograph at a magnification of 200 times ofComposite Particles H according to Example 8.

FIG. 10 is an enlarged SEM photograph at a magnification of 100 times ofa mixture of cellulose and calcium silicate.

DESCRIPTION OF EMBODIMENTS

Hereinafter, an embodiment for implementing the present invention(hereinafter, simply referred to as “the present embodiment”) isdescribed in detail with reference to the drawings when necessary. Thepresent embodiment below is only an example for describing the presentinvention, and is not intended to limit the present invention to thecontents below. Moreover, the attached drawings show an example of theembodiment, and the present embodiment should not be construed to belimited to the drawings. The present invention can be properly modifiedwithout departing from the gist, and implemented.

The composite particles according to the present embodiment comprise acellulose and an inorganic compound formed into a composite product andhaving a specific apparent specific volume.

In the present embodiment, the cellulose refers to fibrous materialscontaining a natural polymer obtained from natural products. In thepresent embodiment, the cellulose preferably has a crystal structure ofa cellulose type I. Preferably, the cellulose has an average width of 2to 30 μm and an average thickness of 0.5 to 5 μm. If the average widthand average thickness of the cellulose are within the ranges above,preferably, the pore within the particle can be sufficiently developedby forming a composite product. More preferably, the cellulose has anaverage width of 2 to 25 μm and an average thickness of 1 to 5 μm.

The cellulose in the present invention includes microcrystallinecellulose. The microcrystalline cellulose used in the present inventionis a white crystalline powder obtained by partially depolymerizingα-cellulose obtained as pulp obtained from a fibrous plant with mineralacid, and purifying the partially depolymerized product. Themicrocrystalline cellulose has various grades. In the present invention,the microcrystalline cellulose having a polymerization degree of 100 to450 is preferable. As a commercially available product, “Ceolus” PHgrade, “Ceolus” KG grade, and “Ceolus” UF grade (all made by Asahi KaseiChemicals Corporation) can be used. The UF grade is most preferable.

Preferably, the cellulose has a volume average particle size of 10 to100 μm. The volume average particle size is preferably 10 to 50 μm, andmore preferably 10 to 40 μm.

The cellulose preferably has an average polymerization degree of 10 to450. The average polymerization degree is more preferably 150 to 450.

In the present embodiment, the inorganic compound is not particularlylimited as long as the inorganic compound is insoluble in water and hasan apparent specific volume of 10 to 50 cm³/g. For example, silicondioxide hydrate, light anhydrous silicic acid, synthetic aluminumsilicate, magnesium hydroxide-aluminum hydroxide co-precipitate,magnesium aluminometasilicate, magnesium aluminosilicate, calciumsilicate, non-crystalline silicon oxide hydrate, magnesium silicate, andmagnesium silicate hydrate are preferable. Preferably, the inorganiccompound has a volume average particle size of 10 to 50 μm because theconcentration of the dispersion liquid of the cellulose and theinorganic compound can be increased. Particularly preferably, theinorganic compound is calcium silicate. Calcium silicate is composed ofCaO, SiO₂, and H₂O. Those represented by the formula2CaO.3SiO₂.mSiO₂.nH₂O (1<m<2, 2<n<3) are preferable. As a commerciallyavailable product, a product name Florite R (made by TokuyamaCorporation), a product name Florite RE (CaO₂ is 50% or more, CaO is 22%or more, available from Eisai Food & Chemical Co., Ltd.), and the likeare available. Calcium silicate is a white powder, and water-insoluble.Calcium silicate is a substance having a high liquid absorbing abilityand good compactibility. The volume average particle size is preferably10 to 40 μm, and more preferably 20 to 30 μm.

From the viewpoint of prevention of sticking, it is thought that whenthe inorganic compound has a larger apparent specific volume andspecific surface area, higher properties can be demonstrated. Lightanhydrous silicic acid has higher physical properties described abovethan those of calcium silicate. As a result of extensive research of aninorganic compound used with the cellulose as the composite particles inthe present invention, however, it was found that the higheststicking-preventing effect is demonstrated in the case where calciumsilicate is used.

The present inventors found out that the inorganic compound and thecellulose are formed into a composite product to make the apparentspecific volume as large as possible; thereby, a retention rate oftocopherol acetate as an index of the liquid retention rate can bemaximized.

Single calcium silicate has a retention rate of tocopherol acetate of800 to 900%, and has a high retention rate among the inorganiccompounds. The retention rate of tocopherol acetate by the cellulose is200 to 250%. For this reason, it is thought that a mixture having aretention rate of more than 800% cannot be obtained even if calciumsilicate is simply mixed with the cellulose. It was found, however, thatthe pore within the particle is sufficiently developed by forming acomposite product to provide a retention rate higher than a simplearithmetic average value.

As an example, the retention rate of tocopherol acetate is comparedbetween a mixture of cellulose and calcium silicate, in which the amountof calcium silicate to be blended is approximately 50%, and thecomposite particles. In the case of the mixture, the logical value ofthe retention rate of tocopherol acetate is approximately 550%.Meanwhile, the composite particles having the same blending amount ofcalcium silicate has an extremely high retention rate of approximately740%.

In other words, by forming the cellulose and calcium silicate into acomposite product, the liquid retention rate is improved, and further,the properties of the cellulose are successfully given to the compositeparticles. Thereby, the composite particles having a high liquidretention rate and given compactibility and fluidity that the cellulosehas can be provided.

Preferably, the composite particles according to the present embodimentcontain 10 to 60 parts by mass of the cellulose and 40 to 90 parts bymass of the inorganic compound. More preferably, the composite particlesaccording to the present embodiment contain 15 to 45 parts by mass ofthe cellulose and 55 to 85 parts by mass of the inorganic compound. Ifthe inorganic compound is 40 parts by mass or more, a largeintraparticle pore volume can be given to the obtained compositeparticles including the cellulose and the inorganic compound to providesufficient liquid retention. Moreover, compression compactibility afterretention of the liquid is improved. If the inorganic compound is 90parts by mass or less, flushing properties can be suppressed, andvariation in the weight of the molded article and the content of theactive ingredient and reduction in compactibility can be suppressed.

In the present embodiment, the composite particles are not simply amixture of the cellulose and the inorganic compound. The compositeparticles need to contain a single aggregate larger than a singleparticle, the aggregate being composed of several particles of thecellulose and several particles of the inorganic compound. When thesurfaces of the composite particles according to the present embodimentare observed using an SEM (magnification of 200 to 500 times), particlesof the cellulose and particles of the inorganic compound are observedindividually. It can be found that several particles of the celluloseand several particles of the inorganic compound collect to form theaggregate (see FIG. 9). For comparison, a simple mixture is shown inFIG. 10. The aggregate is larger than a single particle of the celluloseand a single particle of the inorganic compound. Meanwhile, in thesimple mixture of the cellulose powder and the inorganic compoundpowder, primary particles of the cellulose and primary particles of theinorganic compound individually exist, and no aggregate is formed. Forthis reason, in the case of the simple mixture, high compactibility andfluidity as demonstrated by the composite particles according to thepresent embodiment are not obtained. Formation of the compositeparticles can be determined by observation with an SEM, or the weightproportion of the particles remaining on a sieve when the particles aresieved with the sieve having an opening of 75 μm. If the proportion ofthe particles remaining on the 75 μm sieve is 5 to 70% by weight, andpreferably 10 to 70% by weight, it is determined that the compositeparticles are formed. The composite particles can have pores formedwithin the particle. Thereby, the composite particles can carry theamount of the liquid ingredient more than the amount of the liquidingredient that can be carried by individual particles of the celluloseand individual particles of the inorganic compound. As formation of thecomposite product is progressed, the amount of the pores within theparticles is increased, leading to a higher ability to carry the liquidingredient. For example, the degree of formation of the compositeproduct can be measured by comparing the retention rate of tocopherolacetate. In the simple physical mixture of the cellulose and theinorganic compound, the retention rate of tocopherol acetate is only anarithmetic average value based on the composition ratio of the celluloseand the inorganic compound. Meanwhile, as formation of the compositeproduct is progressed, the amount of the pores within the particles isincreased. For this reason, the composite particles have a higherretention rate of tocopherol acetate.

The composite particles according to the present embodiment need to havean apparent specific volume of 7 to 13 cm³/g. At an apparent specificvolume of 7 cm³/g or more, the liquid retention rate is improved. At anapparent specific volume of 13 cm³/g or less, increase in flushingproperties can be suppressed, and variation in the content of the activeingredient and reduction in compactibility can be suppressed. Morepreferably, the apparent specific volume is 8 to 12 cm³/g.

The composite particles according to the present embodiment preferablyhave a pore size of 0.003 to 1 μm. Here, the pore size means the size ofthe pore on the surface of the composite particle. More preferably, thepore size is 0.05 to 0.5 μm.

The composite particles according to the present embodiment preferablyhave a pore volume of 1.9 to 3.9 cm³/g. Here, the pore volume means thevolume of fine pores that the composite particles have. A pore volume of1.9 cm³/g or more improves the liquid retention rate. At a pore volumeof 3.9 cm³/g or less, increase in flushing properties can be suppressed,and variation in the content of the active ingredient and reduction incompactibility can be suppressed. More preferably, the pore volume is 2to 3.5 cm³/g.

The pore volume contributes to the compression compactibility of thecomposite particles and the liquid retention of the molded article. At alarge pore volume, the composite particles are likely to be crushedduring compression, leading to improved plastic deformability andenhanced hardness of the molded article. Moreover, a large pore volumepromotes penetration of the liquid into the composite particles, leadingto improved liquid retention.

Preferably, the composite particles according to the present embodimenthave a porosity of 15 to 50%. Here, the porosity means a proportion ofthe pore volume to the volume of the composite particles. A porosity of15% or more provides a high liquid retention rate, thus it ispreferable. A porosity of 50% or less can suppress increase in flushingproperties and reduction in compactibility, thus it is preferable. Morepreferably, the porosity is 20 to 40%.

The composite particles according to the present embodiment preferablyhave a weight average particle size of 30 to 250 μm. From the viewpointof fluidity, the weight average particle size is preferably 30 μm ormore. From the viewpoint of suppression in separation and segregation,the weight average particle size is preferably 250 μm or less. Morepreferably, the weight average particle size is 40 to 100 μm. Here,separation and segregation mean that the active ingredient is notuniformly mixed with the composite particles, and that a uniformly mixedstate is not kept.

The composite particles according to the present embodiment preferablyhave a retention rate of tocopherol acetate of 500 to 1000%. At a highretention rate of tocopherol acetate, namely, a high liquid retentionrate, the content of the active ingredient in the molded article can beincreased. At a retention rate of tocopherol acetate less than 500%, theamount of the liquid to be carried is small. From the viewpoint ofliquid retention, the retention rate of tocopherol acetate is preferablyas high as possible, but approximately 1000% at best. The retention rateof tocopherol acetate is more preferably 600 to 1000%, and particularlypreferably 700 to 1000%.

From the viewpoint of fluidity, the composite particles according to thepresent embodiment preferably have a repose angle of 45° or less. Therepose angle is preferably as small as possible, and the lower limit isnot particularly limited. From the viewpoint of suppression inseparation and segregation of the active ingredient during continuouscompression at a high speed, the repose angle is preferably 25°. Morepreferably, the repose angle is 25 to 40°. Similarly, from the viewpointof fluidity, preferably, the composite particles after retention of theliquid have a repose angle of 45° or less, and preferably 25 to 40°.

The composite particles according to the present embodiment preferablyhave a hardness of 200 to 340 N. Here, the hardness is a value obtainedby measurement of a cylindrical molded article obtained by compressing0.5 g of the composite particles at a pressure of 10 MPa with a punchhaving a circular flat surface having a diameter of 1.1 cm by aSchleuniger hardness tester.

Preferably, the composite particles according to the present embodimentfurther include starch. Starch has binding properties, thus contributesto keeping a composite state of the cellulose and the inorganiccompound. Thereby, a granulation state is fixed. Accordingly, additionof starch is preferable. As starch, for example, dextrin, solublestarch, corn starch, potato starch, partly pregelatinized starch,pregelatinized starch, and the like can be used. Those having bindingproperties are preferable. As starch contributing to improvement indisintegration properties, a “SWELSTAR (trademark) WB-1 (made by AsahiKasei Chemicals Corporation)” is particularly preferable because theouter shell is a glue ingredient having binding properties and the innershell is a disintegrable particle. 5 parts by mass to 15 parts by massof starch is preferably contained based on 100 parts by mass of thecomposite particles including starch. At this time, 85 to 95 parts bymass of the microcrystalline cellulose and the inorganic compound intotal are preferably contained.

The composite particles according to the present embodiment have a largeapparent specific volume, a high liquid retention rate, and highfluidity. Further, the composite particles according to the presentembodiment can be suitably used for a direct tableting method and a wettableting method. The composite particles according to the presentembodiment also have reduced scattering properties and high operabilityto prevent tableting problems such as sticking and capping.

The composite particles according to the present embodiment areparticularly suitable for an active ingredient having low fluidity anddifficulties to provide hardness of the tablet. Specific examplesthereof include essence powders of over-the-counter drugs such as coldmedicines and Kampo medicines, and drugs easy to be deactivated by acompression force or friction with an excipient such as enzymes andproteins.

The composite particles according to the present embodiment are alsosuitable for tablets easy to have tableting problems such as breakage orchips of the surface of the tablet, peel off from the inside, andcracks. Specific examples of the tablets include small tablets,non-circular deformed tablets having a portion such as a constriction ofan edge to which a compression force is difficult to be uniformlyapplied, tablets containing a large amount of various drugs, and tabletscontaining coating granules.

Hereinafter, a method for producing the composite particles according tothe present embodiment is described.

The composite particles according to the present embodiment are obtainedby dispersing the cellulose and the inorganic compound in a medium, anddrying the obtained dispersion liquid. Alternatively, the compositeparticles according to the present embodiment can also be obtained bystrongly stirring the cellulose and the inorganic compound by a wetmethod (i.e., formation of a composite product, co-processing).

A raw material for the cellulose is natural products containing acellulose. Examples of the raw material for the cellulose include woodmaterials, bamboo, wheat straw, rice straw, cotton, ramie, bagasse,kenaf, beet, hoya, and bacterial cellulose. The raw material may be ofplant or animal origin, and two or more thereof may be mixed.Alternatively, the raw material may be hydrolyzed. Particularly in thecase of hydrolysis, examples thereof include acid hydrolysis, alkalioxidative decomposition, hydrothermal decomposition, and steamexplosion. These may be used in combination.

In the hydrolysis, a medium for dispersing the solid content containingthe cellulose is not particularly limited as long as the medium isindustrially used. As such medium, water or an organic solvent can beused. Examples of the organic solvent include alcohols such as methanol,ethanol, isopropyl alcohol, butyl alcohol, 2-methyl butyl alcohol, andbenzyl alcohol; hydrocarbons such as pentane, hexane, heptane, andcyclohexane; and ketones such as acetone and ethyl methyl ketone.Particularly, the organic solvent is preferably those used forpharmaceuticals. Examples of the organic solvent include thoseclassified as solvents in “Japanese Pharmaceutical Excipients Directory”(issued by Yakuji Nippo Limited). The medium is preferably water. Waterand the organic solvents may be used in combination. Alternatively, thecellulose and the inorganic compound may be dispersed in one mediumonce, and the medium may be removed; then, the cellulose and theinorganic compound may be dispersed in a different medium.

The cellulose in the present invention preferably has an average widthof 2 to 30 μm and an average thickness of 0.5 to 5 μm. The method is notparticularly limited as long as it is a method for tearing the cellulosemainly in the longitudinal length. The average width and averagethickness of the cellulose can be controlled within specific ranges bytreating wood pulp with a high-pressure homogenizer, and when necessary,performing a mechanical treatment such as grinding and sorting, orcombining these two properly. Alternatively, for example, a pulp whosecellulose has an average width of 2 to 30 μm and an average thickness of0.5 to 5 μm may be selected and used. The volume average particle sizeof a water-dispersed cellulose is preferably 10 to 100 μm. The volumeaverage particle size is preferably 10 to 50 μm, and more preferably 10to 40 μm. Patent Literature 3 describes a cellulose for composing inwhich the cellulose dispersed in water has an L/D of 2.0 or more in a 10to 100 μm fraction. As shown in Examples in Patent Literature 3, thecellulose cannot attain a high apparent specific volume as in thepresent application. Further, the cellulose of Patent Literature 3 isinferior to the composite product according to the present inventionwith respect to the pore volume and the retention rate of tocopherolacetate. The cellulose having a specific average width and averagethickness is preferable for increasing the amount of the pores withinthe particles.

Examples of a method for obtaining a cellulose having a volume averageparticle size of 10 to 100 μm in the state of the cellulose dispersed inwater include:

-   i) a method of shearing, grinding, crushing, and pulverizing a    cellulose to adjust a particle size,-   ii) a method of performing a high pressure treatment such as    explosion on a cellulose to separate the cellulose particles in the    direction along their long axis, and when necessary, applying a    shear force to adjust a particle size, and-   iii) a method of performing a chemical treatment on a cellulose to    adjust a particle size.

Any of the methods described above may be used, and two or more methodsdescribed above may be used in combination. The methods i) and ii) maybe performed by a wet method or a dry method. These wet and dry methodsmay be used in combination.

Examples of the methods i) and ii) include shearing methods using astirring blade of a one-direction rotation type, a multi-axis rotationtype, a reciprocal inversion type, a vertical movement type, arotation+vertical movement type, or a piping type such as a portablemixer, a three-dimensional mixer, and a side-wall mixer; a jet typestirring/shearing method such as a line mixer; a treatment method usinga high-shear homogenizer, a high-pressure homogenizer, and an ultrasonichomogenizer; and an axial rotation extrusion type shearing method suchas a kneader.

Particularly, examples of a pulverizing method include a screen typepulverizing method such as a screen mill and a hammer mill, a bladerotation shearing screen type pulverizing method such as a flush mill,an air stream type pulverizing method such as a jet mill, a ball typepulverizing method such as a ball mill and a vibratory ball mill, and ablade stirring type pulverizing method. Two or more methods among themmay be used in combination.

The volume average particle size of the cellulose can also be controlledwithin a desired range by adjusting a condition on a step of hydrolyzingor dispersing the cellulose, particularly, adjusting a stirring forceapplied to the solution containing the cellulose. Generally, if theconcentrations of an acid and an alkali in the hydrolysis solution areincreased or the reaction temperature is increased, the polymerizationdegree of the cellulose is likely to be reduced to provide a smallervolume average particle size of the cellulose in the dispersion liquid.If the stirring force applied to the solution is stronger, the celluloseparticle is likely to have a smaller volume average particle size.

Next, a method for producing a dispersion liquid containing thecellulose and the inorganic compound is described. The dispersion liquidcan be produced by dispersing the cellulose and the inorganic compoundin a medium. Specifically, examples of the method include:

-   i) a method of adding a mixture of the cellulose and the inorganic    compound in a medium to prepare a dispersion liquid,-   ii) a method of adding the inorganic compound to a cellulose    dispersion liquid to prepare a dispersion liquid,-   iii) a method of adding the inorganic compound to a dispersion    liquid prepared by mixing a third ingredient such as starch with    cellulose particles to prepare a dispersion liquid,-   iv) a method of adding the inorganic compound to a mixture of a    third ingredient such as starch and a cellulose dispersion liquid to    prepare a dispersion liquid, and-   v) a method of adding the cellulose to a dispersion liquid having    the inorganic compound added to prepare a dispersion liquid.

A method for adding the respective ingredients is not particularlylimited as long as it is a method usually performed. Specifically,examples of the addition method include those using a small size suctiontransport apparatus, an air transport apparatus, a bucket conveyor, apneumatic transport apparatus, a vacuum conveyer, a vibration typequantitative metering feeder, a spray, a funnel, or the like. Therespective ingredients may be continuously added, or added in batch.

A mixing method is not particularly limited as long as it is a methodusually performed. Specifically, a vessel rotation type mixer such asV-type, W-type, double cone type, and container tack type mixers, astirring type mixer such as high speed stirring type, universal stirringtype, ribbon type, pug type, and Nauta-type mixers, a high speed fluidtype mixer, a drum type mixer, and a fluidized bed type mixer may beused. Alternatively, dispersing methods using vessel shaking type mixersuch as a shaker, and a stirring blade of a one-direction rotation type,a multi-axis rotation type, a reciprocal inversion type, a verticalmovement type, a rotation+vertical movement type, or a piping type suchas a portable mixer, a three-dimensional mixer, a side-wall mixer, a jettype stirring/dispersing method such as a line mixer, a treatment methodusing a high-shear homogenizer, a high-pressure homogenizer, or anultrasonic homogenizer, and an axial rotation extrusion type shearingmethod such as a kneader may be used, for example. Two or more methodsamong them may be used in combination.

The concentration of the cellulose, inorganic compound, and starch inthe dispersion liquid obtained by the above-described operation ispreferably 5 to 40% by mass. From the viewpoint of fluidity of thecomposite particles obtained by drying the dispersion liquid, theconcentration is preferably 5% by mass or more. From the viewpoint ofcompression compactibility, the concentration is preferably 40% by massor less. The concentration is more preferably 5 to 30% by mass, andstill more preferably 5 to 20% by mass.

The dispersion liquid obtained by the above-described operation is driedto obtain the composite particles according to the present embodiment. Adrying method is not particularly limited. Examples thereof includelyophilization, spray drying, drum drying, shelf drying, air streamdrying, and vacuum drying. Two or more methods among them may be used incombination. A spraying method during spray drying may be any spraydrying method such as a disc type drying method, a pressure nozzle typedrying method, a compressed two-fluid nozzle type drying method, and acompressed four-fluid nozzle type drying method. Two or more methodsamong them may be used in combination.

During the spray drying, a slight amount of a water-soluble polymer anda surfactant may be added in order to reduce the surface tension of thedispersion liquid. In order to accelerate the vaporization rate of themedium, a foaming agent or a substance to generate a gas may be added,or a gas may be added to the dispersion liquid. Specific examples of thewater-soluble polymer, the surfactant, the foaming agent, the substanceto generate a gas, and the gas are shown below, respectively. Thewater-soluble polymer, the surfactant, and the substance to generate agas may be added before drying, and the order of addition is notparticularly limited. Two or more of water-soluble polymers, surfactantsand the substances to generate a gas respectively may be used incombination.

Examples of the water-soluble polymer include water-soluble polymersdescribed in “Japanese Pharmaceutical Excipients Directory” (issued byYakuji Nippo Limited) such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyacrylic acid, carboxyvinyl polymers, polyethyleneglycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,acacia, and starch paste.

Examples of the surfactant include those classified as a surfactant in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as phosphoruslipid, glycerin fatty acid ester,polyethylene glycol fatty acid ester, sorbitan fatty acid ester,polyoxyethylene hardened castor oil, polyoxyethylene cetyl ether,polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether,polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitanmonolaurate, polysorbate, sorbitan monooleate, glyceride monostearate,monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitanmonostearate, polyoxyethylene sorbitan monooleate, sorbitanmonopalmitate, and sodium lauryl sulfate.

Examples of the foaming agent include foaming agents described in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as tartaric acid, sodium hydrogencarbonate, potato starch,anhydrous citric acid, medical soap, sodium lauryl sulfate, lauric aciddiethanolamide, and Lauromacrogol.

Examples of the substance to generate a gas include bicarbonates thatgenerate a gas by pyrolysis such as sodium hydrogen carbonate andammonium hydrogen carbonate; and carbonates that react with an acid togenerate a gas such as sodium carbonate and ammonium carbonate. In useof the carbonates, the carbonates are preferably used with an acid.Examples of the acid include organic acids such as citric acid, aceticacid, ascorbic acid, and adipic acid; proton acids such as hydrochloricacid, sulfuric acid, phosphoric acid, and nitric acid; and Lewis acidssuch as boron fluoride. Particularly, those used in pharmaceuticals andfoods are preferable.

As the gas, gases such as nitrogen, carbon dioxide, liquefied petroleumgas, and dimethyl ether may be impregnated into the dispersion liquid.

The composite particles according to the present embodiment are formedby simultaneously drying the cellulose and the inorganic compound in thestate where the inorganic compound exists in the dispersion liquidcontaining the cellulose. It is thought that if the medium is vaporizedin the state where the cellulose and the inorganic compound areuniformly associated, capillary condensation acts to aggregate thecellulose and the inorganic compound densely. Even if only the celluloseis dried and the inorganic compound is added to and mixed with the driedcellulose, or only the inorganic compound is dried and the cellulose isadded to and mixed with the dried inorganic compound, a compositeproduct is not formed, thus the aggregate structure cannot be obtained.In the case where the cellulose in the dispersion liquid has a specificaverage width and average thickness, the cellulose has a largesuppressing effect on excessive aggregation of particles caused bycapillary condensation during drying, and can provide a large porevolume within the composite particles. When the composite particlesaccording to the present embodiment are produced, cellulose particlesand inorganic compound particles also remain in the dried powders. Thesecellulose particles and inorganic compound particles may be used as theyare without separation.

The molded article according to the present embodiment is obtained bymolding the composite particles according to the present embodiment andan active ingredient. Hereinafter, the molded article according to thepresent embodiment is described.

In the molded article, the proportion of the active ingredient to beused is in the range of 0.001 to 99%, and the proportion of thecomposite particles to be used is in the range of 1 to 99.999%. From theviewpoint of ensuring an amount effective in treatment, the proportionof the active ingredient is preferably 0.001% or more. From theviewpoint of practical hardness, friability, and disintegrationproperties, the proportion of the active ingredient is preferably 99% orless. More preferably, the molded article contains 1 to 90% of thecomposite particles. In the case where the active ingredient is aliquid, tableting problems such as sticking and capping occur. For thisreason, the content of the active ingredient in the molded article islimited. The composite product according to the present invention hashigh liquid retention and compactibility, and can be blended with morethan 20% of a liquid ingredient. The proportion of the liquid ingredientis preferably 21 to 50%, and particularly preferably 21 to 30%. Thelargest content of tocopherol acetate in the commercially availablemolded articles at present is 100 mg/500 mg of the total amount of thetablet. No commercially available molded articles contain more than 20%of tocopherol acetate. By use of the composite product according to thepresent invention, at a blending amount of the liquid ingredient of 21to 50%, the molded article can be downsized in the range of 250 to 480mg. Moreover, at a weight of a tablet of 500 mg, the amount of theliquid ingredient can be increased in the range of 105 to 250 mg. Theamount of the liquid ingredient is preferably 120 to 200 mg, and morepreferably 120 to 150 mg.

The molded article according to the present embodiment can be processedby a known method such as granulation, sizing, and tableting.Particularly, the composite particles according to the presentembodiment are suitable for molding by tableting. If the compositeparticles according to the present embodiment and the active ingredientare contained in the ranges as described above, a molded article havingsufficient hardness can be produced by the direct tableting method. Inaddition to the direct tableting method, the composite particlesaccording to the present embodiment are also suitable for a dry granulecompression method, a wet granule compression method, a compressionmethod with extragranular addition of an excipient, a method ofproducing a multicore tablet using a tablet which is compressed inadvance as an inner core, and a method of layering a plurality of moldedarticles compressed in advance and compressing the layered moldedarticles again to produce a multilayer tablet.

In the present embodiment, examples of the active ingredient includeingredients for a medicament, ingredients for health food, pesticideingredients, fertilizer ingredients, livestock food ingredients, foodingredients, cosmetic ingredients, dyes, flavoring agents, metals,ceramics, catalysts, and surfactants. Ingredients for a medicament andingredients for health food are suitable active ingredients.

The ingredients for a medicament are used in substances orallyadministered such as antipyretic analgesic anti-inflammatory, sedativehypnotic, drowsiness preventing, dizziness suppressing, children'sanalgesic, stomachic, antacid, digestive, cardiotonic, antiarrhythmic,hypotensive, vasodilator, diuretic, antiulcer, intestinalfunction-controlling, bone-building, antitussive expectorant,antiasthmatic, antimicrobial, pollakiuria-improving, analeptic drugs,and vitamins. Active pharmaceutical ingredients may be used alone, ortwo or more of ingredients may be used in combination. Specifically,examples of the medicinal ingredients can include ingredients for amedicament described in “Japanese Pharmacopeia,” “JapanesePharmaceutical Codex (JPC),” “USP,” “NF,” and “EP” such as aspirin,aspirin aluminium, acetaminophen, ethenzamide, sasapyrine, salicylamide,lactylphenetidin, isotibenzyl hydrochloride, diphenylpyralinehydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride,triprolidine hydrochloride, tripelenamine hydrochloride, thonzylaminehydrochloride, fenethazine hydrochloride, methdilazine hydrochloride,diphenhydramine salicylate, carbinoxamine diphenyldisulfonate,alimemazine tartrate, diphenhydramine tannate, diphenylpyralineteoclate, mebhydrolin napadisylate, promethazine methylenedisalicylate,carbinoxamine maleate, chlorpheniramine dl-maleate, chlorpheniramined-maleate, difeterol phosphate, alloclamide hydrochloride, cloperastinehydrochloride, pentoxyverine citrate (carbetapentane citrate),tipepidine citrate, dibunate sodium, dextromethorphan hydrobromide,dextromethorphan-phenolphthalic acid, tipepidine hibenzate,chloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate,noscapine hydrochloride, noscapine, di-methylephedrine hydrochloride,dl-methylephedrine saccharin salt, potassium guaiacolsulfonate,guaifenesin, caffeine and sodium benzoate, caffeine, anhydrous caffeine,vitamin B1 and its derivatives and their salts, vitamin B2 and itsderivatives and their salts, vitamin C and its derivatives and theirsalts, hesperidin and its derivatives and their salts, vitamin B6 andits derivatives and their salts, nicotinic acid amide, calciumpantothenate, aminoacetic acid, magnesium silicate, synthetic aluminumsilicate, synthetic hydrotalcite, magnesia oxide,dihydroxyaluminum-aminoacetate (aluminum glycinate), aluminium hydroxidegel (as dried aluminium hydroxide gel), dried aluminium hydroxide gel,aluminium hydroxide-magnesium carbonate mixed dried gel, aluminiumhydroxide-sodium hydrogen carbonate coprecipitation products, aluminiumhydroxide-calcium carbonate-magnesium carbonate coprecipitationproducts, magnesium hydroxide-potassium aluminum sulfate coprecipitationproducts, magnesium carbonate, magnesium aluminometasilicate, ranitidinehydrochloride, cimetidine, famotidine, naproxen, diclofenac sodium,piroxicam, azulene, indometacin, ketoprofen, ibuprofen, difenidolhydrochloride, diphenylpyraline hydrochloride, diphenhydraminehydrochloride, promethazine hydrochloride, meclizine hydrochloride,dimenhydrinate, diphenhydramine tannate, fenethazine tannate,diphenylpyraline teoclate, diphenhydramine fumarate, prometthazinemethylenedisalicylate, scopolamine hydrobromide, oxyphencycliminehydrochloride, dicyclomine hydrochloride, methixene hydrochloride,atropine methylbromide, anisotropine methylbromide, scopolaminemethylbromide, methyl-1-hyoscyamine bromide, methylbenactyzium bromide,belladonna extract, isopropamide iodide,diphenylpiperidinomethyldioxolan iodide, papaverine hydrochloride,aminobenzoic acid, cesium oxalate, ethyl piperidinoacetylaminobenzoate,aminophyllin, diprophylline, theophylline, sodium hydrogen carbonate,fursultiamine, isosorbide nitrate, ephedrine, cefalexin, ampicillin,sulfixazole, sucralfate, allyl isopropylacetyl urea, bromovalerylureaand the like, ephedra herb, Nandina fruit, yellow bark, polygala root,licorice, platycodon root, plantago seed, plantago herb, senega root,fritillaria bulb, fennel, phellodendron bark, coptis rhizome, zedoary,matricaria, cassia bark, gentian, oriental bezoar, beast gall(containing bear bile), adenophorae radix, ginger, atractylodes lancearhizome, clove, citrus unshiu peel, atractylodes rhizome, earthworm,panax rhizome, ginseng, japanese valerian, moutan bark, zanthoxylumfruit and extracts thereof, insulin, vasopressin, interferon, urokinase,serratio peptidase, and somatostatin. One selected from the above may beused alone, or two or more ingredients selected from the above may beused in combination.

The ingredients for health food are not limited as long as these are aningredient blended for the purpose of augmenting. Examples thereofinclude powdered green juice, aglycone, agaricus, ashwagandha,astaxanthin, acerola, amino acids (valine, leucine, isoleucine, lysine,methionine, phenylalanine, threonine, tryptophan, histidine, cystine,tyrosine, arginine, alanine, aspartic acid, powdered seaweed, glutamine,glutamic acid, glycin, proline, serine, etc.), alginic acid, ginkgobiloba extract, sardine peptides, turmeric, uronic acid, echinacea,Siberian ginseng, oligosaccharides, oleic acid, nucleoproteins, driedskipjack peptides, catechin, potassium, calcium, carotenoid, garciniacambogia, L-carnitine, chitosan, conjugated linoleic acid, Aloearborescens, Gymnema sylvestre extract, citric acid, Orthosiphonstamineus, glycerides, glycenol, glucagon, curcumin, glucosamine,L-glutamine, chlorella, cranberry extract, Uncaria tomentosa, germanium,enzymes, Korean ginseng extract, coenzyme Q10, collagen, collagenpeptides, coleus blumei, chondroitin, powdered psyllium husks, Crataegifructus extract, saponin, lipids, L-cystine, Japanese basil extract,citrimax, fatty acids, phytosterol, seed extract, spirulina, squalene,Salix alba, ceramide, selenium, St. John's wort extract, soy isoflavone,soy saponin, soy peptides, soy lecithin, monosaccharides, proteins,chaste tree extract, iron, copper, docosahexaenoic acid, tocotrienol,nattokinase, Bacillus natto culture extract, sodium niacin, nicotineacid, disaccharides, lactic acid bacterium, garlic, saw palmetto,sprouted rice, pearl barley extract, herb extract, valerian extract,pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitaminA and A2, vitamin B1, B2 and B6, vitamin B12, vitamin C, vitamin D,vitamin E, vitamin K, hydroxytyrosol, bifidobacterium, beer yeast,fructo oligosaccharides, flavonoid, Butcher's broom extract, blackcohosh, blueberry, prune concentrate, proanthocyanidin, proteins,propolis, bromelain, probiotics, phosphatidylcholine,phosphatidylserine, β-carotene, peptides, safflower extract, Grifolafrondosa extract, maca extract, magnesium, milk thistle, manganese,mitochondria, mineral, mucopolysaccharides, melatonin, Fomes yucatensis,powdered melilot extract, molybdenum, vegetable powder, folic acid,lactose, lycopene, linolic acid, lipoic acid, phosphorus, lutein,lecithin, rosmarinic acid, royal jelly, DHA, and EPA

The active ingredient may be any form of powdery, crystalline, liquid,and semi-solid forms. A liquid active ingredient is suitable. The activeingredient may be coated or encapsulated for control of elution,reduction in bitterness, or the like. In use of the active ingredient,the active ingredient may be dissolved, suspended, or emulsified in amedium. A plurality of active ingredients may be used in combination.

Examples of the liquid active ingredient include ingredients for amedicament described in “Japanese Pharmacopeia,” “JPC,” “USP,” “NF,” and“EP” such as teprenone, indomethacin-farnesyl, menatetrenone,phytonadione, vitamin A oil, fenipentol, vitamins such as vitamin D andvitamin E, higher unsaturated fatty acids such as DHA (docosahexaenoicacid), EPA (eicosapentaenoic acid), and liver oil, coenzyme Qs, andoil-soluble flavorings such as orange, lemon, and peppermint oils.Moreover, vitamin E has various homologues and derivatives thereof.Examples thereof can include dl-α-tocopherol, dl-α-tocopherol acetate,tocopherol acetate, and d-α-tocopherol acetate. The homologues andderivatives of vitamin E are not particularly limited as long as theseare a liquid at 25° C. These having a viscosity in the range of 3 to10000 mPa·s are preferable. If a homologue or derivative of vitamin Ehas a proper viscosity, it preferably provides a good balance betweencompactibility and fluidity of the composite particles after the liquidingredient is carried by the composite product. Tocopherol acetate isparticularly preferable.

Examples of the semi-solid active ingredient can include, Kampomedicines or crude drug extracts such as earthworm, licorice, cassiabark, peony root, moutan bark, japanese valerian, zanthoxylum fruit,ginger, citrus unshiu peel, ephedra herb, nandina fruit, yellow bark,polygala root, platycodon root, plantago seed, plantago herb, shorttubelycoris, senega root, fritillaria bulb, fennel, phellodendron bark,coptis rhizome, zedoary, matricaria, gentian, oriental bezoar, beastgall, adenophorae radix, ginger, atractylodes lancea rhizome, clove,citrus unshiu peel, atractylodes rhizome, panax rhizome, ginseng,kakkonto, keishito, kousosan, saiko-keishito, shosaikoto, shoseiryuto,bakumondoto, hangekobokuto, and maoto, an oyster meat essence, propolisor an extract thereof, and coenzyme Qs.

The crystal of the active ingredient after molding may have the sameshape as that before molding, or may have a shape different from thatbefore molding. Preferably, the shape of the crystal after molding isthe same as that before molding from the viewpoint of stability.

In addition to the active ingredient and the composite particles, themolded article according to the present embodiment freely containsexcipients such as an excipient, a disintegrant, a binder, a fluidizingagent, a lubricant, a corrigent, a flavoring agent, a coloring agent,and a sweetener when necessary. Two or more excipients among them may beused in combination.

Examples of the excipient include those classified as an excipient in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as acrylated starch, L-asparagic acid, aminoethyl sulfonicacid, aminoacetate, wheat gluten (powder), acacia, powdered acacia,alginic acid, sodium alginate, pregelatinized starch, inositol, ethylcellulose, ethylene-vinyl acetate copolymer, sodium chloride, olive oil,kaolin, cacao butter, casein, fructose, light gravel granule,carmellose, carmellose sodium, silicon dioxide hydrate, dry yeast, driedaluminum hydroxide gel, dried sodium sulfate, dried magnesium sulfate,agar, agar powder, xylitol, citric acid, sodium citrate, disodiumcitrate, glycerin, calcium glycerophosphate, sodium gluconate,L-glutamine, clay, clay grain, croscarmellose sodium, crospovidone,magnesium aluminosilicate, calcium silicate, magnesium silicate, lightanhydrous silicic acid, light liquid paraffin, cinnamon powder,microcrystalline cellulose, microcrystalline cellulose-carmellosesodium, microcrystalline cellulose (grain), brown rice malt, syntheticaluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour,wheat starch, wheat germ powder, rice powder, rice starch, potassiumacetate, calcium acetate, cellulose acetate phthalate, safflower oil,white beeswax, zinc oxide, titanium oxide, magnesium oxide,β-cyclodextrin, dihydroxyaluminum aminoacetate,2,6-dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid,potassium hydrogen tartrate, plaster, sucrose fatty acid ester,magnesium hydroxide-aluminum hydroxide co-precipitate, aluminumhydroxide gel, aluminum hydroxide/sodium hydrogen carbonatecoprecipitate, magnesium hydroxide, squalane, stearyl alcohol, stearicacid, calcium stearate, polyoxyl stearate, magnesium stearate, purifiedgelatine, purified shellac, purified sucrose, purified sucrose sphericalgranulated powder, cetostearyl alcohol, polyethylene glycol 1000monocetyl ether, gelatine, sorbitan fatty acid ester, D-sorbitol,tricalcium phosphate, soybean oil, unsaponified soy bean, soy beanlecithin, powdered skim milk, talc, ammonium carbonate, calciumcarbonate, magnesium carbonate, neutral anhydrous sodium sulfate, lowsubstitution degree hydroxypropylcellulose, dextran, dextrin, naturalaluminum silicate, corn starch, powdered tragacanth, silicon dioxide,NEWKALGEN 204, calcium lactate, lactose, par filler 101, white shellac,white vaseline, white clay, sucrose, sucrose/starch spherical granulatedpowder, naked barley green leaf extract powder, dried powder of bud andleaf juice of naked barley, honey, paraffin, potato starch,semi-digested starch, human serum albumin, hydroxypropyl starch,hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, phytic acid, glucose, glucose hydrate,partially pregelatinized starch, pullulan, propylene glycol, starchsyrup of reduced malt sugar powder, powdered cellulose, pectin,bentonite, sodium polyacrylate, polyoxyethylene alkyl ethers,polyoxyethylene hydrogenated castor oil, polyoxyethylene (105)polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30)glycol, sodium polystyrene sulfonate, polysorbate, polyvinylacetaldiethylamino acetate, polyvinylpyrrolidone, polyethylene glycol(molecular weight of 1500 to 6000), maltitol, maltose, D-mannitol, watercandy, isopropyl myristate, anhydrous lactose, anhydrous dibasic calciumphosphate, anhydrous dibasic calcium phosphate granulated substance,magnesium aluminometasilicate, methyl cellulose, cottonseed powder,cotton oil, haze wax, aluminum monostearate, glyceryl monostearate,sorbitan monostearate, pharmaceutical carbon, peanut oil, aluminumsulfate, calcium sulfate, granular corn starch, liquid paraffin,dl-malic acid, calcium monohydrogen phosphate, calciumhydrogenphosphate, calcium hydrogenphosphate granulated substance,sodium hydrogenphosphate, potassium dihydrogen phosphate, calciumdihydrogen phosphate, and sodium dihydrogen phosphate.

Examples of the disintegrant include those classified as a disintegrantin “Japanese Pharmaceutical Excipients Directory” (issued by YakujiNippo Limited) such as croscarmellose sodium, carmellose, carmellosecalcium, carmellose sodium, celluloses such as low substitution degreehydroxypropylcellulose, starches such as sodium carboxymethyl starch,hydroxypropyl starch, rice starch, wheat starch, corn starch, potatostarch, and partly pregelatinized starch, and synthetic polymers such ascrospovidone and crospovidone copolymer.

Examples of the binder include those classified as a binder in “JapanesePharmaceutical Excipients Directory” (issued by Yakuji Nippo Limited)sugars such as sucrose, glucose, lactose and fructose, sugar alcoholssuch as mannitol, xylitol, maltitol, erythritol, and sorbitol,water-soluble polysaccharides such as gelatine, pullulan, carrageenan,locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin,sodium alginate, and acacia, celluloses such as microcrystallinecellulose, powdered cellulose, hydroxypropylcellulose and methylcellulose, starches such as cornstarch, potato starch, pregelatinizedstarch and starch paste, synthetic polymers such aspolyvinylpyrrolidone, carboxyvinyl polymer and polyvinyl alcohol, andinorganic compounds such as calcium hydrogenphosphate, calciumcarbonate, synthetic hydrotalcite, and magnesium aluminosilicate.

Examples of the fluidizing agent include those classified as afluidizing agent in “Japanese Pharmaceutical Excipients Directory”(issued by Yakuji Nippo Limited) such as silicon compounds such assilicon dioxide hydrate and light anhydrous silicic acid, wet silicassuch as sodium silicates, calcium silicate, and sodium stearyl fumarate(trade name “PRUV” made by JRS).

Examples of the lubricant include those classified as a lubricant in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as magnesium stearate, calcium stearate, stearic acid,sucrose fatty acid ester, talc, Fujicalin, and sodium stearyl fumarate(trade name “PRUV” made by JRS).

Examples of the corrigent include those classified as a corrigent in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as glutamic acid, fumaric acid, succinic acid, citricacid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodiumchloride, and 1-menthol.

Examples of the flavoring agent include those classified as aromaticsand flavoring agents in “Japanese Pharmaceutical Excipients Directory”(issued by Yakuji Nippo Limited) such as orange, vanilla, strawberry,yogurt, menthol, oils such as fennel oil, cinnamon bark oil, orange peeloil, and peppermint oil, and green tea powder.

Examples of the colorant include those classified as a colorant in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as edible dyes such as edible red 3, edible yellow 5, andedible blue 1, sodium copper chlorophyllin, titanium oxide, andriboflavin.

Examples of the sweetener include those classified as a sweetener in“Japanese Pharmaceutical Excipients Directory” (issued by Yakuji NippoLimited) such as aspartame, saccharin, dipotassium glycyrrhizinate,stevia, maltose, maltitol, starch syrup, and powdered sweet hydrangealeaf.

Examples of a form of the molded article include solid preparations suchas tablets, powders, subtle granules, granules, and pills when themolded article is used for pharmaceuticals.

Hereinafter, a tablet is described as a suitable specific example of themolded article according to the present embodiment.

The tablet refers to a molded article containing the composite particlesaccording to the present embodiment, the active ingredient, and whennecessary other excipients, and obtained by tableting. The compositeparticles according to the present embodiment have high compressioncompactibility. Accordingly, a tablet for practical use can be obtainedat a relatively low compression force. The composite particles accordingto the present embodiment can be molded and tableted at a lowcompression force. For this reason, the tablet can keep gaps (waterintroducing pipes) inside thereof. Such a tablet is suitable for anorally disintegrating tablet rapidly disintegrated in an oral cavity. Inaddition, the composite particles according to the present embodimentare suitable for multilayer tablets and core tablets obtained bycompressing ingredients in several compositions at one stage or at multistages. The composite particles according to the present embodiment havehigh effects of imparting high hardness to the molded article, andsuppressing tableting problems, peel off between interlayers, andcracks. Further, the composite particles according to the presentembodiment themselves have high dividing properties, thus a tabletformed of the composite particles according to the present embodiment iseasy to be divided uniformly. Accordingly, the composite particlesaccording to the present embodiment are also suitable for a scoredtablet and the like.

The composite particles according to the present embodiment have aporous structure, and the composite particles themselves have highretention of the liquid ingredient such as fine particle drugs,suspended drugs, and liquid ingredients. For this reason, the moldedarticle of the composite particles according to the present embodimentalso has high retention of the liquid ingredient. For this reason, whena suspended or liquid ingredient is layered and coated on the tablet,the tablet also has a preventive effect on peel off of an outer layersuch as a coating layer. Accordingly, the composite particles accordingto the present embodiment are also suitable for a layered tablet and atablet having a coating layer (such as sugar-coated tablets, and tabletshaving a layered ingredient such as calcium carbonate).

Hereinafter, a method of producing a molded article containing theactive ingredient and the composite particles according to the presentembodiment is described. This is only an example, and the presentinvention is not limited to the description below.

Examples of a method for molding a molded article include a method ofmixing the active ingredient with the composite particles according tothe present embodiment, and compressing the mixture. At this time, theexcipients other than the above-described active ingredient may beblended when necessary. The order of addition is not particularlylimited. Examples of the method include:

-   1) a method in which the active ingredient is mixed with the    composite particles according to the present embodiment and, when    necessary, an excipient in batch, and the mixture is compressed;-   2) a method in which the active ingredient is mixed with an    excipient such as a fluidizing agent or a lubricant, and then mixed    with the composite particles according to the present invention and,    when necessary, an additional excipient, and the mixture is    compressed; and-   3) a method in which a lubricant is further mixed with the mixed    powder for compression obtained by 1) or 2), and the obtained    mixture is compressed.

A method for adding ingredients is not particularly limited as long asthe method is a method usually performed. The ingredients may be addedcontinuously or in batch using a small size suction transport apparatus,an air transport apparatus, a bucket conveyor, a pneumatic transportapparatus, a vacuum conveyer, a vibration type quantitative meteringfeeder, a spray, a funnel, or the like.

A mixing method is not particularly limited as long as the method is amethod usually performed. A vessel rotation type mixer such as V-type,W-type, double cone type, and container tack type mixers, or a stirringtype mixer such as high speed stirring type, universal stirring type,ribbon type, pug type, and Nauta-type mixers, a high speed fluid typemixer, a drum type mixer, or a fluidized bed type mixer may be used.Alternatively, a vessel shaking type mixer such as a shaker can be used.

A compression method is not particularly limited as long as the methodis a method usually performed. The method may be a method of compressingingredients into a desired shape using a die and a punch, or a method ofcompressing ingredients into a sheet form in advance and cutting thesheet into a desired shape. A usable compression machine is, forexample, a compressor such as a hydrostatic press, a roller type presssuch as a briquetting roller type press or a smoothing roller typepress, a single-punch tableting machine, or a rotary tableting machine.

In the case where an active ingredient poorly-soluble in water is used,generally, examples of the compression method include:

-   A) a method in which the active ingredient is pulverized, and mixed    with the composite particles according to the present embodiment    and, when necessary, other ingredient; and the obtained mixture is    compressed; and-   B) a method in which the active ingredient is dissolved or dispersed    in water, an organic solvent, or a solubilizing agent, and mixed    with the composite particles according to the present embodiment    and, when necessary, other excipients; when necessary, water or the    organic solvent is removed; and the obtained mixture is compressed.

The composite particles according to the present embodiment are suitablefor the above-described method B). In the method B), the activeingredient poorly-soluble or insoluble in water is once dissolved ordispersed. For this reason, the active ingredient can be carried by thecomposite particles securely. Thereby, separation or elution of theactive ingredient during compression can be prevented to suppresssticking. The composite particles according to the present embodimenthave high compression compactibility and fluidity. For this reason, inthe case of the method B), the composite particles according to thepresent embodiment can be formed into a tablet at little variation inthe weight by the compression.

The method B) is more suitable in the case where the active ingredientin the drug is used for pharmaceuticals and a liquid medium such aspolyethylene glycol is used in combination as a dispersion medium.Polyethylene glycol or the like is used in order to keep the efficacy ofthe active ingredient which is easily metabolizable in the liver bycoating the active ingredient with polyethylene glycol in the blood whenthe active ingredient is absorbed in a human body.

In the method B), in order to assist dissolution, it is effective to usea water-soluble polymer or a surfactant as a solubilizing agent incombination to disperse the active ingredient in a medium.

The organic solvent is not particularly limited as long as it is usedfor pharmaceuticals. Examples of the organic solvent include thoseclassified as a solvent in “Japanese Pharmaceutical ExcipientsDirectory” (issued by Yakuji Nippo Limited) such as alcohols such asmethanol and ethanol, and ketones such as acetone. Two or more organicsolvents among them are freely used in combination.

Examples of the water-soluble polymer as the solubilizing agent in themethod B) include water-soluble polymers described in “JapanesePharmaceutical Excipients Directory” (issued by Yakuji Nippo Limited)such as hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylalcohol, polyvinylpyrrolidone, methylcellulose, ethylcellulose, acacia,and starch paste. Two or more water-soluble polymers among them arefreely used in combination.

Examples of oils and fats as the solubilizing agent include oils andfats described in “Japanese Pharmaceutical Excipients Directory” (issuedby Yakuji Nippo Limited) such as monoglyceride stearate, triglyceridestearate, sucrose stearic acid ester, paraffins such as liquid paraffin,carnauba wax, hydrogenated oils such as hydrogenated castor oil, castoroil, stearic acid, stearyl alcohol, and polyethylene glycol. Two or moreoils and fats among them are freely used in combination.

Examples of the surfactant in the solubilizing agent include thoseclassified as a surfactant in “Japanese Pharmaceutical ExcipientsDirectory” (issued by Yakuji Nippo Limited) such as phospholipid,glycerin fatty acid ester, polyethylene glycol fatty acid ester,sorbitan fatty acid ester, polyoxyethylene hardened castor oil,polyoxyethylene cetyl ether, polyoxyethylene stearyl ether,polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropyleneglycol, polyoxyethylene sorbitansan monolaurate, polysorbate, sorbitanmonooleate, glyceride monostearate, monooxyethylene sorbitansanmonopalmitate, monooxyethylene sorbitan monostearate, polyoxyethylenesorbitan monooleate, sorbitan monopalmitate, and sodium lauryl sulfate.Two or more surfactants among them are freely used in combination.

In the method B), a dissolving or dispersing method is not particularlylimited as long as it is a dissolving or dispersing method usuallyperformed. A stirring/mixing method using a stirring blade of aone-direction rotation type, a multi-axis rotation type, a reciprocalinversion type, a vertical movement type, a rotation+vertical movementtype, or a piping type such as a portable mixer, a three-dimensionalmixer, and a side-wall mixer; a jet type stirring/mixing method such asa line mixer; a gas-blowing stirring/mixing method; a mixing methodusing a high-shear homogenizer, a high-pressure homogenizer, or anultrasonic homogenizer; or a vessel shaking type mixing method using ashaker, or the like may be used.

The composite particles according to the present embodiment have aporous structure, and the composite particles themselves have highretention of the drug. For this reason, the particles carrying the drugwithin pores may be used as they are as fine granules, may be granulatedas used for granules, or may be compressed.

A method for carrying a drug is not particularly limited as long as itis a known method. Examples of the method include:

-   i) a method in which the composite particles according to the    present embodiment are mixed with a fine particle drug to be carried    within pores;-   ii) a method in which the composite particles according to the    present embodiment are mixed with a powdery drug at a high speed to    be forcibly carried within pores;    iii) a method in which the composite particles according to the    present embodiment are once mixed with a drug prepared as a solution    or a dispersion liquid, the drug is carried within pores, and the    obtained one is dried if necessary;-   iv) a method in which the composite particles according to the    present embodiment are mixed with a sublimation drug, and the    mixture is heated and/or the pressure is reduced, thereby, the drug    is sublimated and adsorbed within pores; and-   v) a method in which the composite particles according to the    present embodiment are mixed with a drug before or during heating,    and molten.

Two or more methods as described above may be used in combination.

Besides use as the tablet thus compressed, the composite particlesaccording to the present embodiment may be used as granules or powdersparticularly in order to improve fluidity, blocking resistance, andaggregation resistance because the composite particles according to thepresent embodiment also have high retention of a solid or liquidingredient. The above-described fine granules and the granules may befurther coated.

As a method for producing granules and powders, the same effect isobtained even if any of dry granulation, wet granulation, heatinggranulation, spray drying, and microencapsulation is used, for example.

Moreover, the composite particles according to the present embodimenthave proper moisture retention and oil retention. Accordingly, otherthan the excipient, the composite particles according to the presentembodiment can be used as a core particle for layering and coating, andhave a suppressing effect on aggregation of particles in a layering orcoating step. The layering and coating may be a dry method or a wetmethod.

The composite particles according to the present embodiment are alsoused for foods such as confectionery, health foods, texture-improvingagents, and dietary fiber-reinforcing agent, cake makeups, bath agents,animal drugs, diagnostic reagents, agricultural chemicals, fertilizers,and ceramic catalysts, and the like.

EXAMPLES

The present invention is described based on Examples. Embodiments of thepresent invention are not limited to the description of these Examples.In Examples and Comparative Examples, methods for measuring physicalproperties are as follows.

(1) Average Width of Cellulose (μm)

Cellulose primary particles formed of a natural cellulose were driedwhen necessary, and placed on a sample stage to which a carbon tape wasattached. Platinum palladium was vacuum deposited (the membranethickness of the deposited membrane at this time was 20 nm or less).Using a JSM-5510LV (trade name) made by JASCO Corporation, the celluloseprimary particles were observed at an accelerating voltage of 6 kV andat a magnification of 250 times. A short diameter in the vicinity of thecenter of a long diameter of a cellulose particle was considered as arepresentative width, and the width was measured. The widths of threerepresentative cellulose primary particles were measured, and theaverage was defined as the average width of the cellulose.

(2) Average Thickness of Cellulose (μm)

Cellulose primary particles formed of a natural cellulose were driedwhen necessary, and placed on a sample stage to which a carbon tape wasattached. Gold was vacuum deposited. Then, using a focused ion beamprocessing apparatus (made by Hitachi, Ltd., FB-2100 (trade name)), across section of the cellulose primary particles was cut out with a Gaion beam, and observed at an accelerating voltage of 6 kV and amagnification of 1500 times. A shorter diameter in the cross section ofthe cellulose particles was measured, and the obtained value was definedas the thickness (the cross section was cut out such that a longerdiameter corresponded to the short diameter of the cellulose particle).The thicknesses of three representative cellulose primary particles weremeasured, and the average value thereof was defined as the thickness ofthe cellulose.

(3) Volume Average Particle Size of Cellulose or Inorganic Compound (μm)

The cellulose or the inorganic compound was dispersed in water toprepare a dispersion liquid. The volume average particle size of thecellulose or inorganic compound was defined as a 50% cumulative volumeof particles in the dispersion liquid measured using a laser diffractionparticle size distribution analyzer (made by HORIBA, Ltd., LA-910 (tradename)) wherein a measurement mode at 4 stirrings and 5 circulations wasselected and the measurement condition was the transmittance of around85%, an ultrasonic treatment for 1 minute, and the refractive index of1.20. The measurement value as obtained above does not always correlatewith the particle size distribution of dried particles obtained by thefollowing Ro-Tap type apparatus because the measurement principles aretotally different from each other. The volume average particle sizemeasured by laser diffraction is measured from volume frequenciesdepending on the long diameter of fibrous particles while the weightaverage particle size obtained by the Ro-Tap type apparatus depends onthe short diameter of fibrous particles because the obtained powder isshaken on a sieve and fractionated. Thus, there is a case that the valuemeasured by the laser diffraction type apparatus depending on the longdiameter of fibrous particles is larger than that measured by the Ro-Taptype apparatus depending on the short diameter of fibrous particles.

(4) Weight Average Particle Size of Composite Particles (μm)

10 g of a powder sample (dried composite particles) was sieved for 10minutes using a Ro-Tap type sieve shaker (made by Taira Kosakusho Ltd.,trade name “Sieve Shaker type A”) with a JIS standard sieve (Z8801-1987)to measure particle size distribution, and the weight average particlesize of the powder sample was defined as a 50% cumulative weightparticle size. The particle size distribution was determined using a 300μm sieve, a 212 μm sieve, a 177 μm sieve, a 150 μm sieve, a 106 μmsieve, a 75 μm sieve, and a 38 μm sieve.

(5) Pore Size (μm), Intraparticle Pore Volume (cm³/g), Porosity (%)

Pore distribution was determined using a trade name “Autopore type 9520”made by SHIMADZU Corporation according to mercury porosimetry.Approximately 0.03 g to 0.05 g of each of sample powders used in themeasurement was placed in a standard cell, and the pore distribution wasmeasured twice on the condition of an initial pressure of 7 kPa(corresponding to approximately 1 psia, pore diameter of approximately18 μm). From the obtained pore distribution, a volume at a pore size inthe specific range of 0.003 to 1.0 μm was calculated as the pore volume.The porosity is the proportion of the pore volume to the volume of thesample when mercury is pressed into pores having a diameter ofapproximately 180 μm at an initial atmospheric pressure.

(6) Repose Angle (°)

Using a Sugihara-type repose angle measuring instrument (slit size depth10×width 50×height 140 mm, a protractor was set at a position of 50 mmin width), a sample was continuously deposited in a measurement partlittle by little (3 g/min as a guideline) with an electromagnetic feeder(MF-1 type/TSUTSUI SCIENTIFIC INSTRUMENTS CO., LTD.). Thus, an inclinedsurface was formed. Immediately when an excessive sample started fallingand the inclined surface became substantially linear, the feeder wasturned off. The angle of the inclined surface was measured with the setprotractor, and defined as the repose angle.

(7) Method for Compressing Sample

0.5 g of a sample was weighed, and placed in a die (Kikusui SeisakushoLtd., a material used was SUS2,3). The sample was compressed with apunch having a circular flat surface having a diameter of 1.1 cm (madeby Kikusui Seisakusho Ltd., a material of SUS2,3 was used) until thepressure reached 10 MPa (made by AIKOH ENGINEERING CO., LTD., a tradename “PCM-1A”, compression rate of 1 cm/min), and kept at a targetpressure for 10 seconds to produce a cylindrical molded article.

(8) Hardness of Tablet (N)

Using a Schleuniger hardness tester (made by Freund Corporation, tradename “8M type”), a load was applied to a cylindrical molded article or atablet in the diameter direction of the cylindrical molded article ortablet, and the load when the cylindrical molded article or tablet wasbroken was measured. The hardness of the tablet was defined as theaverage value obtained from ten samples.

(9) Apparent Specific Volume (cm³/g)

A 25 cm³ container was set in a Scott Volumeter (made by VWR SCIENTIFIC,S64985 type). Next, using an electromagnetic feeder (MF-1 type/TSUTSUISCIENTIFIC INSTRUMENTS CO., LTD.), a sample was put into the containerat a rate of 10 to 20 g/min. When the sample overflowed from the setcontainer, the container was taken out. An excessive amount of thesample was leveled off, and the mass of the sample was measured. Theapparent specific volume was defined as a value (cm³/g) obtained bydividing the volume of the container (25 cm³) by the mass of the sample.The sample was measured twice, and the average value was used.

(10) Retention Rate of Tocopherol Acetate (%)

2 g of a sample was weighed. While the sample was kneaded, tocopherolacetate (viscosity at 25° C.: 3300 mPa·s) was dropped on the samplelittle by little. The end point was defined as the amount of the liquidwhen the liquid eluted on the surface of the sample. The retention rateof tocopherol acetate is represented by the following expression:retention rate of tocopherol acetate (%)=amount of dropped liquid g/2 gof sample×100 The measurement value was defined as the average value ofmeasurement values obtained from two samples.

(11) The Number of Capping to be Occurred

50 tablets after tableting were arbitrarily sampled, and the number ofthe tablets cracked or partially peeled was counted.

(12) Sticking Occurrence Rate (%)

50 tablets were examined visually, and the number of the tablets havingpeel-off or damages on the surface was counted. The sticking occurrencerate (%) was defined as the proportion of the number of tablets havingsticking.

(13) Weight CV Value

10 tablets after tableting were arbitrarily sampled, and the weights ofthe samples were measured. From the average value and standard deviationof the measured values, the weight CV value was defined as weight CVvalue=(standard deviation/average value)×100[%]. A larger weight CVvalue causes larger variation in the weight, leading to increase invariation in the content of the drug and reduced yield of products. At aweight CV value of more than 1.0%, practical problems arise.

(14) Scanning Electron Microscope Photograph (Hereinafter, Abbreviatedto SEM)

Measurement was performed using an electron microscope (made by JEOL,Ltd., JSM-551OLV type). A sample was mounted on a sample moving stage.According to a gold deposition method (AUTO FINE COATER, made by JEOL,Ltd., JFC-1600 type), the surface of the sample is thinly and uniformlycoated with metal particles. Then, the sample moving stage was installedwithin a sample chamber. The inside of the sample chamber was made to bevacuum. The sample position was irradiated with an electron beam, and anenlarged image of the portion to be observed was output.

(15) Average Polymerization Degree

The average polymerization degree was defined as the value measured by acopper ethylenediamine solution viscosity method described in theIdentification Test for Microcrystalline Cellulose (3) of The JapanesePharmacopoeia, Fourteenth Edition.

(16) L/D of Cellulose Particles Dispersed in Water

The average L/D of cellulose particles dispersed in water was measuredas follows. Using a JIS standard sieve (Z8801-1987), an aqueousdispersion liquid of the cellulose was passed through a 75 μm sieve. Inthe particles remaining on a 38 μm sieve, an optical microscope image ofthe remaining particles was subjected to an image analysis processing(made by Inter Quest Co., Ltd., apparatus: Hyper 700, software:Imagehyper). The L/D of a particle was defined as the ratio of a longerside to a shorter side (longer side/shorter side) of the rectanglehaving the smallest area among rectangles circumscribed about theparticle. The average L/D of the particle was obtained using the averagevalue of L/D obtained from at least 100 particles.

Example 1

A broad leaf tree was subjected to known pulping and bleachingtreatments to obtain a pulp (the average width of the cellulose primaryparticle was approximately 19 μm, and the average thickness of thecellulose primary particle was approximately 3 μm). 4.5 kg of thechipped pulp and 30 L of a 0.2% hydrochloric acid aqueous solution wereput into a low speed stirrer (made by Ikebukuro Horo Kogyo Co., Ltd.,trade name, 30LGL reactor). While the chipped pulp and the aqueoussolution were stirred, hydrolysis was performed at 124° C. for 1 hour toobtain an acid insoluble residue (hereinafter, referred to as a Wetcake). The volume average particle size of the cellulose particle wasmeasured by a laser diffraction/scattering particle size distributionanalyzer (made by HORIBA, Ltd., trade name “LA-910”) at a refractiveindex of 1.20. The obtained volume average particle size was 25 μm.

Pure water was introduced into a plastic bucket. While pure water wasstirred by a 3-1 motor, the Wet cake was added and mixed. Next, calciumsilicate (made by Tokuyama Corporation, product name: Florite R, volumeaverage particle size of 25 μm) was added and mixed. The mass ratio wascellulose/calcium silicate=28.6/71.4 (based on the solid content), andthe concentration of the total solid content was approximately 8.5% bymass. The obtained mixture was spray dried (dispersion liquid feed rateof 6 kg/hr, inlet temperature of 180 to 220° C., outlet temperature of70 to 95° C., number of rotation of an atomizer of 15000 rpm) to obtainComposite Particles A. The physical properties of Composite Particles Aare shown in Table 1.

Examples 2 and 3

A broad leaf tree was subjected to known pulping treatment and bleachingtreatments to obtain a pulp (the average width of the cellulose primaryparticle was approximately 19 μm, and the average thickness of thecellulose primary particle was approximately 3 μm). 4.5 kg of thechipped pulp and 30 L of a 0.2% hydrochloric acid aqueous solution wereput into a low speed stirrer (made by Ikebukuro Horo Kogyo Co., Ltd.,trade name, 30LGL reactor). While the chipped pulp and the aqueoussolution were stirred, hydrolysis was performed at 124° C. for 1 hour toobtain an acid insoluble residue (hereinafter, referred to as a Wetcake). The volume average particle size of the cellulose particle wasmeasured by a laser diffraction/scattering particle size distributionanalyzer (made by HORIBA, Ltd., trade name “LA-910”) at a refractiveindex of 1.20. The obtained volume average particle size was 25 μm.

Pure water was introduced into a plastic bucket. While pure water wasstirred by a 3-1 motor, starch (made by Asahi Kasei ChemicalsCorporation, trade name “SWELSTAR” WB-1) was added and mixed. Next, theWet cake was added and mixed. Next, calcium silicate (made by TokuyamaCorporation, product name: Florite R, volume average particle size of 25μm) was added and mixed. The mass ratio was starch/cellulose/calciumsilicate=10/20/1970 (based on the solid content), and the concentrationof the total solid content was approximately 8.5% by mass (pH was 10.2).The obtained mixture was spray dried (dispersion liquid feed rate of 6kg/hr, inlet temperature of 180 to 220° C., outlet temperature of 70 to95° C., number of rotation of an atomizer of 15000 rpm, 30000 rpm).Thus, Composite Particles B (number of rotation of an atomizer of 15000rpm) and Composite Particles C (number of rotation of an atomizer of30000 rpm) were obtained. The physical properties of Composite ParticlesB and C are shown in Table 1.

Examples 4 and 5

A broad leaf tree was subjected to known pulping and bleachingtreatments to obtain a pulp (the average width of the cellulose primaryparticle was approximately 19 μm, and the average thickness of thecellulose primary particle was approximately 3 μm). 4.5 kg of thechipped pulp and 30 L of a 0.2% hydrochloric acid aqueous solution wereput into a low speed stirrer (made by Ikebukuro Horo Kogyo Co., Ltd.,trade name, 30LGL reactor). While the chipped pulp and the aqueoussolution were stirred, hydrolysis was performed at 124° C. for 1 hour toobtain an acid insoluble residue (hereinafter, referred to as a Wetcake). The volume average particle size of the cellulose particle wasmeasured by a laser diffraction/scattering particle size distributionanalyzer (made by HORIBA, Ltd., trade name “LA-910”) at a refractiveindex of 1.20. The obtained volume average particle size was 25 μm.

Pure water was introduced into a plastic bucket. While pure water wasstirred by a 3-1 motor, the Wet cake was added and mixed. Next, calciumsilicate (made by Tokuyama Corporation, product name: Florite R, volumeaverage particle size of 25 μm) was added and mixed. The mass ratio wascellulose/calcium silicate=20/80 (based on the solid content), and theconcentration of the total solid content was approximately 8.5% by mass.The mixture was spray dried (dispersion liquid feed rate of 6 kg/hr,inlet temperature of 180 to 220° C., outlet temperature of 70 to 95° C.,number of rotation of an atomizer of 15000 rpm and 30000 rpm). Thus,Composite Particles D (number of rotation of an atomizer of 15000 rpm),and Composite Particles E (number of rotation of an atomizer of 30000rpm) were obtained. The physical properties of Composite Particles D andE are shown in Table 1.

Examples 6 and 7

Composite particles F (number of rotation of an atomizer of 15000 rpm)and Composite Particles G (number of rotation of an atomizer of 30000rpm) were obtained in the same manner as in Examples 2 and 3 except thatthe mass ratio was starch/cellulose/calcium silicate=5/40/55 (based onthe solid content). The physical properties of Composite Particles F andG are shown in Table 1.

Examples 8 and 9

Composite Particles H (number of rotation of an atomizer of 15000 rpm)and Composite Particles I (number of rotation of an atomizer of 30000rpm) were obtained in the same manner as in Examples 2 and 3 except thatthe mass ratio was starch/cellulose/calcium silicate=7/43/50 (based onthe solid content), and the concentration of the total solid content was9.3% by mass. The physical properties of Composite Particles H and I areshown in Table 1.

Examples 10 and 11

Composite particles J (number of rotation of an atomizer of 15000 rpm)and Composite Particles K (number of rotation of an atomizer of 30000rpm) were obtained in the same manner as in Examples 4 and 5 except thatthe mass ratio was cellulose/calcium silicate=60/40 (based on the solidcontent), and the concentration of the total solid content was 11.7% bymass. The physical properties of Composite Particles J and K are shownin Table 1.

Examples 12 and 13

Composite particles L (number of rotation of an atomizer of 8000 rpm)and Composite Particles M (number of rotation of an atomizer of 30000rpm) were obtained in the same manner as in Examples 2 and 3 except thatthe mass ratio was starch/cellulose/calcium silicate=3/60/37 (based onthe solid content), the concentration of the total solid content was11.7% by mass, and the number of rotation of an atomizer was 8000 rpmand 30000 rpm. The physical properties of Composite Particles L and Mare shown in Table 1.

Example 14

Composite particles N (number of rotation of an atomizer of 15000 rpm)were obtained in the same manner as in Example 2 except that the massratio was starch/cellulose/calcium silicate=2.5/72.5/25 (based on thesolid content), and the concentration of the total solid content was11.7% by mass. The physical properties of Composite Particles N areshown in Table 1.

Example 15

Composite particles O (number of rotation of an atomizer of 30000 rpm)were obtained in the same manner as in Example 5 except that the massratio was cellulose/light anhydrous silicic acid=50/50 (based on thesolid content), and the concentration of the total solid content was 4%by mass. The physical properties of Composite Particles O are shown inTable 1.

Example 16

Composite particles P (number of rotation of an atomizer of 15000 rpm)were obtained in the same manner as in Example 4 except that the massratio was cellulose/magnesium aluminometasilicate=30/70 (based on thesolid content), and the concentration of the total solid content was 5%by mass. The physical properties of Composite Particles P are shown inTable 1.

Example 17

Composite particles Q (number of rotation of an atomizer of 15000 rpm)were obtained in the same manner as in Example 4 except that the massratio was cellulose/magnesium silicate hydrate=50/50 (based on the solidcontent), and the concentration of the total solid content was 5% bymass. The physical properties of Composite Particles Q are shown inTable 1.

TABLE 1 Inorganic Cellulose compound volume volume Cellulose Celluloseaverage average Inorganic Starch average average particle particleCellulose compound Kind of parts width thickness size size parts byparts by inorganic by Table 1 [μm] [μm] [μm] [μm] mass mass compoundmass Example 1 A 19 3 25 25 28.6 71.4 Calcium silicate Ca — Example 2 B19 3 25 25 20 70 Calcium silicate Ca 10 Example 3 C 19 3 25 25 20 70Calcium silicate Ca 10 Example 4 D 19 3 25 25 20 80 Calcium silicate ca— Example 5 E 19 3 25 25 20 80 Calcium silicate Ca — Example 6 F 19 3 2525 40 55 Calcium silicate Ca 5 Example 7 G 19 3 25 25 40 55 Calciumsilicate Ca 5 Example 8 H 19 3 25 25 43 50 Calcium silicate Ca 7 Example9 I 19 3 25 25 43 50 Calcium silicate Ca 7 Example 10 J 19 3 25 25 60 40Calcium silicate Ca — Example 11 K 19 3 25 25 60 40 Calcium silicate Ca— Example 12 L 19 3 25 25 60 37 Calcium silicate Ca 3 Example 13 M 19 325 25 60 37 Calcium silicate Ca 3 Example 14 N 19 3 25 25 72.5 25Calcium silicate Ca 2.5 Example 15 O 19 3 20 0.016 50 50 Light anhydrous— silicic acid Example 16 P 19 3 25 12 30 70 Magnesium —aluminometasilicate Example 17 Q 19 3 50 0.07 50 50 Magnesium silicate —hydrate Mg Weight Retention Apparent average rate of Hardness specificRepose Pore particle tocopherol of volume angle Volume Porosity sizeacetate tablet Table 1 [cm³/g] [°] [cm³/g] [%] [μm] [%] [N] Example 1 A10.8 35 2.71 33.1 48 860 240 Example 2 B 10.4 34.5 2.70 32.4 38 830 233Example 3 C 10.7 37.5 2.81 33.1 55 860 244 Example 4 D 11.5 35 3.15 35.531 915 325 Example 5 E 11.6 36.5 3.15 35.5 32 875 312 Example 6 F 8.7 321.97 27.4 80 703 243 Example 7 G 8.8 34 2.09 28.2 60 738 261 Example 8 H9.4 30 2.32 29.8 90 725 264 Example 9 I 8.7 33 2.05 28.0 70 760 240Example 10 J 8.2 35 1.84 26.5 65 575 239 Example 11 K 7.7 39 1.63 25.050 520 220 Example 12 L 7.1 35 1.43 23.8 210 590 190 Example 13 M 7.235.5 1.48 24.1 61 530 200 Example 14 N 7.1 38.5 1.44 23.9 49 485 236Example 15 O 12.5 41 1.50 25.1 29 500 150 Example 16 P 10.5 37 1.55 24.940 510 170 Example 17 Q 11.6 38 1.21 20.2 38 450 148

Reference Example 1

100 g of pure water was introduced into a stainless steel jug. Whilepure water was stirred by a 3-1 motor, calcium silicate (made byTokuyama Corporation, product name: Florite R, volume average particlesize of 25 to 30 μm) was added little by little with a dispensing spoonand stirred. When the amount of calcium silicate added reached 10.7 g,stirring became impossible.

Reference Example 2

Pure water was introduced into a stainless steel jug. While pure waterwas stirred by a 3-1 motor, the Wet cake obtained in Example 1 was addedand mixed. Next, while SiO₂ (trade name: Aerosil 200, made by NipponAerosil Co., Ltd., volume average particle size of 0.016 μm) was addedlittle by little with a dispensing spoon, the materials were stirred andmixed. The mass ratio was cellulose/light anhydrous silicicacid=29.3/70.7 (based on the solid content), and the concentration ofthe total solid content was 8.5% by mass (pH was 10.2). The obtainedproduct was gluey, and could not be spray dried.

Reference Example 3

Pure water was introduced into a stainless steel jug. While pure waterwas stirred by a 3-1 motor, the Wet cake obtained in Example 1 was addedand mixed. Next, magnesium aluminometasilicate (trade name: Neusilin,made by Fuji Chemical Industry Co., Ltd.) was mixed. The mass ratio wascellulose/magnesium aluminometasilicate=31.0/69.0 (based on the solidcontent), and the concentration of the total solid content was 11.7% bymass (pH was 10.2). The obtained product was creamy, and could not bespray dried.

Comparative Example 1

The physical properties of calcium silicate (made by TokuyamaCorporation, product name: Florite R, volume average particle size of 25μm) are shown in Table 2.

Comparative Example 2

Composite particles R were obtained in the same manner as in Example 4except that the mass ratio was starch/cellulose/calciumsilicate=2.5/72.5/25 (based on the solid content), and the concentrationof the total solid content was 11.7% by mass. The physical properties ofComposite Particles R are shown in Table 2.

Comparative Example 3

2 kg of a chipped commercially available dissolved pulp (acicular treepulp, average width of the cellulose primary particle was approximately39 μm, average thickness of the cellulose primary particle wasapproximately 8 μm) and 30 L of a 0.4% hydrochloric acid aqueoussolution were put into a low speed stirrer (made by Ikebukuro Horo KogyoCo., Ltd., trade name, 30LGL reactor). While the chipped pulp and theaqueous solution were stirred, hydrolysis was performed at 116° C. for 1hour to obtain an acid insoluble residue (the volume average particlesize of the cellulose dispersed particle was 51 and L/D was 3.4). Theobtained acid insoluble residue and silicon dioxide (made by TokuyamaCorporation, trade name, FINESEAL, volume average particle size of 5 μm)as a water insoluble inorganic compound were introduced into a 90 Lplastic bucket at an amount ratio of 30/70 (based on the solid content).Pure water was added such that the concentration of the total solidcontent became 20% by weight. While the materials were stirred by a 3-1motor, the materials were neutralized with aqueous ammonia (pH afterneutralization was 7.5 to 8.0). The obtained product was spray dried(dispersion liquid feed rate of 6 kg/hr, inlet temperature of 180 to220° C., outlet temperature of 50 to 70° C., number of rotation of anatomizer of 30000 rpm) to obtain Composite Particles S (corresponding toExample 2 in Patent Literature 3). The physical properties of CompositeParticles S are shown in Table 2.

Comparative Example 4

2 kg of a chipped commercially available pulp (acicular tree pulp,average width of the cellulose primary particle was approximately 39 μm,average thickness of the cellulose primary particle was approximately 8μm) and 30 L of a 0.2% hydrochloric acid aqueous solution were put intoa low speed stirrer (made by Ikebukuro Horo Kogyo Co., Ltd., trade name,30 LGL reactor). While the chipped pulp and the aqueous solution werestirred, hydrolysis was performed at 116 ° C. for 1 hour to obtain anacid insoluble residue (the volume average particle size of thecellulose dispersed particle was 72 μM, and L/D was 4.0). The acidinsoluble residue (solid content) and talc (made by Wako Pure ChemicalIndustries, Ltd., prepared so as to have a volume average particle sizeof 5 μm) were introduced into a 90 L plastic bucket at an amount ratioof 98/2 (based on the solid content). Pure water was added such that theconcentration of the total solid content became 10% by weight. While thematerials were stirred by a 3-1 motor, the materials were neutralizedwith aqueous ammonia (pH after neutralization was 7.5 to 8.0). Theobtained product was spray dried in the same manner as that inComparative Example 3 to obtain Composite Particles T (corresponding toexample 6 in Patent Literature 3). The physical properties of CompositeParticles T are shown in Table 2.

Comparative Example 5

Ceolus PH-101 (made by Asahi Kasei Chemicals Corporation) was used as amicrocrystalline cellulose. The cellulose and calcium silicate at a massratio of cellulose/calcium silicate=28.6/71.4 were sufficiently mixed ina plastic bag for 3 minutes to obtain Mixture U of cellulose/calciumsilicate (the mixture having the largest amount of silicic acid to beblended which is described in Patent Literature 4). The physicalproperties of Mixture U are shown in Table 2.

Comparative Example 6

Ceolus PH-101 (made by Asahi Kasei Chemicals Corporation) was used as amicrocrystalline cellulose. The cellulose and calcium silicate at a massratio of cellulose/calcium silicate=71.4/28.6 were sufficiently mixed ina plastic bag for 3 minutes to obtain Mixture V of cellulose/calciumsilicate (the mixture having the smallest amount of silicic acid to beblended which is described in Patent Literature 4). The physicalproperties of Mixture V are shown in Table 2.

TABLE 2 Inorganic Cellulose Cellulose compound Inorganic average averageCellulose particle Cellulose compound Starch width thickness particlesize size parts by parts by Kind of inorganic parts by [μm] [μm] [μm][μm] mass mass compound mass Comparative — — — — 25 — 100 Calciumsilicate Ca — Example 1 Comparative R 19 3 22-27 25 72.5 25 Calciumsilicate Ca 2.5 Example 2 Comparative S 39 8 51 5 30 70 Silicon dioxide— Example 3 Comparative T 39 8 72 5 98 2 Talc — Example 4 Comparative U39 8 38 25 28.6 71.4 Calcium silicate Ca — Example 5 Comparative V 39 838 25 71.4 28.6 Calcium silicate Ca — Example 6 Retention ApparentAverage rate of specific Repose Pore particle tocopherol Hardness volumeangle volume Porosity size acetate of tablet [cm³/g] [°] [cm³/g] [%][μm] [%] [N] Comparative — 13.7 40 3.95 41.0 56 885 348 Example 1Comparative R 6.9 40.5 1.37 23.3 50 440 215 Example 2 Comparative S 5.132 1.25 22.1 52 400 45 Example 3 Comparative T 6 45 0.29 17.2 45 204 110Example 4 Comparative U 11 42 1.88 27.1 29 687 265 Example 5 ComparativeV 7.4 38 1.00 20.4 39 390 145 Example 6<SEM Photograph>

Using a “JSM-5510LV type” electron microscope made by JEOL, Ltd.,Composite Particles B, D, G, I, K, and M were observed by SEM.

It is found that the particle has relatively few irregularities on thesurface, and has a shape close to a sphere in Composite Particles B inExample 2 (see FIG. 1), Composite Particles D in Example 4 (see FIG. 2),Composite Particles G in Example 7 (see FIG. 3), and Composite ParticlesI in Example 9 (see FIG. 4). It is also found that the cellulose WETcake (see FIG. 5) and calcium silicate in Reference Example 2 (see FIG.6) are formed into a composite product which has gaps. The gaps canprovide a molded article having high liquid retention rate and hardness.

Meanwhile, the particle has irregularities on the surface in CompositeParticles K in Example 11 (FIG. 7) and Composite Particles M in Example13 (see FIG. 8).

<Evaluation of Prevention of Sticking>

Ibuprofen is a representative example of a drug easy to stick. Usingibuprofen, comparison was made about the sticking-preventing effect.Granulated granules having ibuprofen blended were produced by thefollowing method.

In the total amount of ingredients of 1000 g, 45% of ibuprofen (made byAPI Corporation), 38% of lactose hydrate (trade name: lactose 200M, madeby DMV International), and 17% of corn starch (GRDE: ST-C, made byNIPPON STARCH CHEMICAL CO., LTD.) were weighed and mixed in apolyethylene bag for 3 minutes. Then, the mixture was placed in avertical granulator (made by Powrex Corporation, FM-VG-10P type) andmixed (blade at 200 rpm, chopper at 2100 rpm). 200 g of a hydroxypropylcellulose (trade name: HPC-L, made by NIPPON SODA CO., LTD.) 6% solutionwas poured over 30 seconds. Further, the ingredients were mixed(granulated) for 3 minutes, and taken out from the granulator. Next, themixture was dried using a MULTIPLEX (made by Powrex Corporation, MP-01type). The drying was completed when the temperature of exhaust airreached 40° C. Then, a granulated product was extracted. The granulatedproduct was sieved with a sieve having an opening of 710 μm, and used asa test sample (hereinafter, referred to as granulated granules).

Example 18

88% by mass of the granulated granules, 2% by mass of croscarmellosesodium (made by NICHIRIN CHEMICAL INDUSTRIES, LTD.), “KICCOLATE”ND-2HS), and 10% by mass of Composite Particles C of Example 3 weremixed in a polyethylene bag for 3 minutes. Next, based on the totalweight of the mixed powder, 0.5% by mass of magnesium stearate (made byTAIHEI CHEMICAL INDUSTRIAL CO., LTD.) was added, and mixed slowly for 30seconds. Using a rotary tableting machine (made by Kikusui SeisakushoLtd., CLEANPRESS CORRECT 12HUK), the mixed powder was tableted with apunch having a diameter of 0.8 cm and 12R on the condition of the numberof rotation of the turn table of 54 rpm, a compression force of 5 to 15kN, and open feed. Thus, a tablet having a weight of 180 mg wasproduced. The physical properties of the tablet are shown in Table 3.

Example 19

The operation was performed in the same manner as that in Example 18except that Composite Particles C used in Example 18 were replaced byComposite Particles H of Example 8. The physical properties of thetablet are shown in Table 3.

Comparative Example 7

The operation was performed in the same manner as that in Example 18except that Composite Particles C used in Example 18 were replaced bylight anhydrous silicic acid (made by Nippon Aerosil Co., Ltd., Aerosil200). The physical properties of the tablet are shown in Table 3.

Comparative Example 8

The operation was performed in the same manner as that in Example 18except that Composite Particles C used in Example 18 were replaced byComposite Particles S of Comparative Example 3. The physical propertiesof the tablet are shown in Table 3.

Comparative Example 9

The operation was performed in the same manner as that in Example 18except that Composite Particles C used in Example 18 were replaced byComposite Particles T of Comparative Example 4. The physical propertiesof the tablet are shown in Table 3.

Comparative Example 10

The operation was performed in the same manner as that in Example 18except that Composite Particles C used in Example 18 were replaced byMixture U of Comparative Example 5. The physical properties of thetablet are shown in Table 3.

Comparative Example 11

The operation was performed in the same manner as that in Example 18except that Composite Particles C used in Example 18 were replaced byMixture V of Comparative Example 6. The physical properties of thetablet are shown in Table 3.

TABLE 3 Sticking occurrence Number of Items Hardness [N] Mass CV [%]Friability [%] rate [%] cappings occurred Compression force [kN] 5 10 155 10 15 5 10 15 15 15 Example 18 Composite particles C 59 85 102 0.5 0.60.5 0.45 0.15 0.11 0 None Example 19 Composite particles H 70 90 79 0.90.5 0.9 0.16 0.08 0.17 0 None Comparative Light anhydrous silicic 30 5338 2.2 2.1 1.6 0.39 0.43 2.85 0 2 Example 7 acid Comparative Compositeparticles S 20 35 40 1.9 2.3 1.5 2.50 1.90 1.20 5 25 Example 8Comparative Composite particles T 20 48 60 2.8 1.8 3.4 2.40 1.00 0.80 205 Example 9 Comparative Mixture U 26 40 30 1.5 1.4 1.9 1.00 0.90 0.80 1025 Example 10 Comparative Mixture V 20 37 43 1.8 1.6 2.1 1.8 1.20 0.7050 40 Example 11

In Examples 18 and 19, tablets having a practical hardness of 50 N ormore, the weight CV value of 1.0% or less, and no tableting problems(sticking, capping) were obtained. Meanwhile, in Comparative Example 7,tableting problems (no sticking, but two cappings) were occurred. Theweight CV value was more than 1.0%. Accordingly, the tablet inComparative Example 7 is not suitable for practical use. In ComparativeExamples 8 to 11, the weight CV value was more than 1.0%, and tabletingproblems (sticking, capping) were remarkable. Accordingly, the tabletsin Comparative Examples 8 to 11 are not suitable for practical use.

In Comparative Example 9, a practical hardness of 50 N or more wasobtained at the compression force of 15 kN while the friability was 0.8%and did not satisfy the practical level of 0.5% or less.

The disintegrating time of the tablet was measured in the respectivetablets, but no remarkable difference was found among the tablets.

<Method for Producing Emulsion Solution>

360 g of Riken tocopherol acetate (Riken Vitamin Co., Ltd.) as an liquidactive ingredient, Tween 80 (Wako Pure Chemical Industries, Ltd.), and1000 g of pure water were weighed, and stirred and mixed with a TKhomomixer (PRIMIX Corporation, MARK2 2.5 type) at 10000 rpm for 15minutes to produce an emulsified solution.

Example 20

360 g of Composite Particles C of Example 3 was put into a verticalgranulator (made by Powrex Corporation, FM-VG-10P). While CompositeParticles C were mixed on the condition of a blade at 200 rpm and achopper at 2100 rpm, 360 g of the emulsified solution produced above waspoured in 30 seconds. The obtained mixture was granulated for 6 minutes,and discharged. Next, the granulated product was dried with an oven(made by Tabai Espec Corp., ESPEC Oven PV-211), and passed through asieve having an opening of 710 μm (made by Iida Seisakusho K.K., sievefor a test) to obtain a dried product. The dried product was used as atest sample (hereinafter, referred to as VE granules). The repose angleof the VE granules was 35° and good.

35% by mass of the VE granules, 45% by mass of a microcrystallinecellulose (made by Asahi Kasei Chemicals Corporation, UF-711), 18% bymass of anhydrous dibasic calcium phosphate (made by Fuji ChemicalIndustry Co., Ltd., Fujicalin), and 2% by mass of croscarmellose sodium(made by NICHIRIN CHEMICAL INDUSTRIES, LTD, “KICCOLATE” ND-2HS) weremixed in a polyethylene bag for 3 minutes. Next, based on the totalweight of the mixed powder, 2.0% by mass of magnesium stearate (made byTAIHEI CHEMICAL INDUSTRIAL CO., LTD.) was added, and further mixedslowly for 30 seconds. Using a rotary tableting machine (made by KikusuiSeisakusho Ltd., LIBRA2), the mixed powder was tableted using a punchhaving a diameter of 0.8 cm and 12R on the condition of the number ofrotation of the turn table of 30 rpm, the compression force of 2 to 7kN, and open feed to produce a tablet having a weight of 200 mg. Thephysical properties of the tablet are shown in Table 4.

Comparative Example 12

The operation was performed in the same manner as in Example 20 exceptthat Composite Particles C were replaced by calcium silicate (made byTokuyama Corporation, product name: Florite Grade(R), volume averageparticle size (which was measured at the state of aggregated particles)of 25 to 30 μm). The physical properties of the tablet are shown inTable 4. The repose angle of the VE granules was 41°. Fluidity wasinferior to that in the case where Composite Particles C were used.

Comparative Example 13

The operation was performed in the same manner as in Example 20 exceptthat Composite Particles C were replaced by Composite Particles S. Thephysical properties of the tablet are shown in Table 4.

Comparative Example 14

The operation was performed in the same manner as in Example 20 exceptthat Composite Particles C were replaced by Mixture U. The physicalproperties of the tablet are shown in Table 4.

TABLE 4 Items Sticking occurrence rate [%] Compression force [kN] 2 3 45 6 7 Example 20 Composite particles C 0 0 0 Comparative Calciumsilicate 31.0 11.3 75.0 Example 12 Comparative Composite particles SPowder cannot be obtained Example 13 Comparative Mixture U Powder cannotbe obtained Example 14

In Example 20, a tablet having a practical hardness of 50 N or more, aweight CV value of 1.0% or less, and no tableting problems (sticking,capping) were obtained. Meanwhile, in Comparative Example 12, thesticking occurrence rate was not 0 at all of the compression forces.Accordingly, the tablet is not suitable for practical use. InComparative Examples 13 and 14, the retention rate of tocopherol acetatewas low, and powder could not be obtained.

Industrial Applicability

The composite particles according to the present invention haveextremely high compactibility and fluidity. For this reason, thecomposite particles according to the present invention have highuniformity of mixing with the active ingredients when the compositeparticles according to the present invention are used as an excipientmainly in the pharmaceutical field in production of a molded articlecontaining a variety of active ingredients. Moreover, the compositeparticles according to the present invention can keep the compactibilityand fluidity of the particles even after retention of the liquid toprevent tableting problems. In addition, the weight of the moldedarticle according to the present invention is hardly fluctuated. Themolded article according to the present invention has high uniformity ofthe active ingredients contained, high sufficient hardness, and lowfriability.

The invention claimed is:
 1. Composite particles comprising a celluloseand an inorganic compound, wherein an apparent specific volume is 7 to13 cm³/g, and a volume average particle size of the cellulose as awater-dispersed cellulose is 10 to 40 μm, wherein the cellulose has anaverage width of 2 to 30 μm and an average thickness of 0.5 to 5 μm. 2.The composite particles according to claim 1, comprising 10 to 60 partsby mass of the cellulose and 40 to 90 parts by mass of the inorganiccompound.
 3. The composite particles according to claim 1, wherein theinorganic compound is at least one selected from the group consisting ofsilicon dioxide hydrate, light anhydrous silicic acid, syntheticaluminum silicate, magnesium hydroxide-aluminum hydroxideco-precipitate, magnesium aluminometasilicate, magnesiumaluminosilicate, calcium silicate, non-crystalline silicon oxidehydrate, magnesium silicate, and magnesium silicate hydrate.
 4. Thecomposite particles according to claim 1, wherein the inorganic compoundis calcium silicate.
 5. The composite particles according to claim 1,wherein a pore size is 0.003 to 1 μm, and a pore volume is 1.9 to 3.9cm³/g.
 6. The composite particles according to claim 1, wherein aretention rate of tocopherol acetate is 500 to 1000%.
 7. The compositeparticles according to claim 1, wherein a weight average particle sizeis 30 to 250 μm.
 8. The composite particles according to claim 1,further comprising starch.
 9. A molded article comprising the compositeparticles according to claim 1 and an active ingredient.
 10. The moldedarticle according to claim 9, wherein the active ingredient is aningredient for a medicament or an ingredient for health food.
 11. Amolded article comprising composite particles comprising a cellulose andan inorganic compound according to claim 1, and an active ingredient,wherein the active ingredient is a liquid having a viscosity at 25° C.of 3 to 10000 mPa·s, and the molded article contains 105 to 250 mg ofthe active ingredient per 500 mg of one molded article.
 12. The moldedarticle according to claim 11, wherein the liquid ingredient istocopherol acetate.